A. Intravenous Iron Therapy
Iron therapy is necessary to replenish total body iron stores in patients with iron deficiency anemia. Therapeutically-active iron-containing compositions comprise iron in a form capable of increasing the amount of hemoglobin in the blood. Intravenous (IV) is particularly employed for patients who cannot tolerate oral iron therapy, are unable to adequately absorb dietary iron, or who suffer hematopoietic failure.
B. Potential Side Effects of IV Iron Therapy
One iron formulation, iron dextran, has been associated with significant adverse effects. Such effects are reported in approximately 26% of patients receiving iron dextran. See, Gupta et al., Kidney Int., 1999 May; 55(5):1891–8. The underlying cause of the immediate severe reactions is unclear. However, known anaphylactic reactions to dextran have implicated dextran as the cause of the severe reactions to IV iron dextran. IV iron products free of dextran are thought to decrease or avoid these severe reactions.
One product that is dextran-free is sodium ferric gluconate complex in sucrose (FERRLECIT®). Reactions associated with administration of sodium ferric gluconate are mild to moderate and occur at a lower rate compared to reactions associated with iron dextran. The most common reactions associated with sodium ferric gluconate are transient hypotension, flushing, rash, and gastrointestinal symptoms. See, Nissenson et al., Am. J. Kidney Dis. 1999 March; 33(3):471–82. One study comparing iron dextran with sodium ferric gluconate has shown an occurrence of 3.3 allergic episodes per million doses for sodium ferric gluconate and 8.7 allergic episodes per million doses for iron dextran. Id.
C. Purity of Sodium Ferric Gluconate Complexes
Since the 1975 merger of the United States Pharmacopoeia (USP) with the National Formulary (NF) to produce the USP-NF compendial guidelines for drugs, standard identities and analytical protocols have been developed for over 3,800 pharmaceuticals. Still, 35% of marketed pharmaceuticals, including sodium ferric gluconate complex in sucrose, are not included in the USP-NF.
Sodium ferric gluconate complex in sucrose generally contains contaminants including excipients, free gluconate and by-products of the synthesis of the complex which are readily detected by techniques such as gel permeation chromatography (GPC).
A chromatographic method for separating and purifying an iron saccharidic complex product is disclosed in U.S. Patent Application Publications 2002/0076821 and 2003/0153086. A sodium ferric gluconate complex, substantially free of excipients having a molecular weight of less than about 5,000 Daltons, is also disclosed.
Small variations in molecular structure and composition can determine the difference between an active iron complex having no adverse effects, and another iron complex that may induce adverse reactions. See, “Raising the Bar for Quality Drugs”, pp. 26–31, Chemical and Engineering News, American Chemical Society, Mar. 19, 2001, the entire disclosure of which is incorporated herein by reference. There is a reported correlation between toxicity of iron saccharate complexes and higher molecular weight and the variability of size of the complex. See, Fishbane et al., Semin Dial. 2000 Nov–Dec; 13(6):381–4.
A composition of sodium ferric gluconate complex comprising a narrower molecular weight distribution may yield a safer and more efficacious therapy. There exists a need for a sodium ferric gluconate complex preparative method that results in a product with narrower molecular weight distribution as compared to existing compositions.